1. Field of the Invention
The present invention relates to monoclonal antibodies to gp130 protein responsible for transmission of interleukin-6 (IL-6).
2. Related Art
IL-6 binds to interleukin-6 receptor (IL-6R) (Japanese Unexamined Patent Publication (Kokai) No. 2-288898) to form a complex. The complex of the IL-6 and IL-6R binds to gp130 protein which is a membrane protein on a target cell (Japanese Unexamined Patent Publication (Kokai) No. 4-29997) to transmit various physiological actions of IL-6 to a target cell (Taga et al., Cell 58, p573 (1989)).
As a physiological action of IL-6, a platelet increasing action was reported (Ishibashi et al., Blood 74, 1241, 1989), and therefore IL-6 is expected to be a novel pharmaceutical component. On the other hand, it was reported that abnormal production of IL-6 causes various autoimmune diseases, and inhibitors of this physiological action have attracted much attention. (Hirano et al., Immunology Today, 11, 443, 1990). As one such IL-6 inhibitors, it was reported that antibodies to IL-6 provide therapeutic effects on terminal myeloma patients (B. Klein et al., Eur. Cytokine Net. 1, 193, 1990).
As IL-6 inhibitors, in addition to antibodies to IL-6, antibodies to gp130 which is a protein transmitting an IL-6 signal, i.e., physiological activity of IL-6, are anticipated. Moreover, it is reported that the gp130 protein is a signal transmitting protein for oncostatin M which is a cancer cell growth factor and a signal transmitting protein for a leukemia inhibitory factor (LIF) which was originally identified as a leukemia growth inhibitor (Gearing et al., Science, 255, 1434, 1992), and therefore antibodies to gp130 protein are promising as an inhibitor for these physiologically active substances.
As antibodies to gp130 protein, Japanese Unexamined Patent Publication (Kokai) No. 3-219894 describes antibodies AM64 and AM277 prepared from mice immunized with gp130 protein. However, inhibitory effects of the known antibodies such as AM64 and AM277 on IL-6 functions are partial, indicating that the known antibodies could not be used as inhibitors of IL-6. Establishment of hybridomas producing anti-gp130 antibody which can inhibit IL-6 functions as strongly as the known antibody against IL-6 (MH166, see Matsuda et al., Eur. Immunol. 18, 951, (1988).) or IL-6R (PM1, see Hirata et al., 143, 2900, (1989)) seems to be difficult to be accomplished because (1) anti-gp130 monoconal antibody which inhibit IL-6 functions strongly cannot be necessarily prepared, (2) the efficient method of selecting the hybridoma producing desired antibody from a large number of established clones is not known. (It is impossible to check precisely the inhibitory effects on IL-6 functions by using the supernatant containing antibody.) (3) although genetic engineered soluble gp130 lacking transmembrane and cytplasmic regions can be used instead of membrane-purified gp130, it is not reported that such soluble gp130 is suitable as immunogen to prepare above said antibody.